Cisplatin has been used widely in clinical medicine as an antitumor drug since an antitumor effect was discovered for cis-dichlorodiaminoplatin. Rosenberg et al. Nature, 1965, 205: 698; Nature, 1972, 222: 385. Although a drug of this type exhibits therapeutic effects in cancers such as genitourinary cancer, nasopharyngeal cancer, cephalocircular cancer and lung cancer, it is toxic and leads to severe side effects. Some undesirable effects, such as nephrotoxicity, neurotoxicity, ototoxicity, nausea, and vomiting, are all constraints to its dosage and long term use. Carboplatin, one of the second-generation antitumor drugs of platin analogues, has an antitumor spectrum similar to that of cisplatin and is susceptible to cross drug-resistance. The therapeutic effect of carboplatin is slightly inferior to that of cisplatin. Although the toxicity and associated side effects of carboplatin is significantly less than that of cisplatin, myelosuppression still exists, and cisplatin is not stable as an aqueous solution. As a result, active studies in search of highly potent antitumor drugs from platin analogues with low toxicity and broad-spectrum effects have continued.
Dicycloplatin (DCP) is a super molecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined together by hydrogen bonds. The solubility and stability of platinum complexes have a direct bearing on their activity, toxicity and pharmacokinetics. Preclinical studies have shown that DCP overcomes the problem of CBP instability in aqueous solution while maintaining CBP's anticancer effects. Clinical evaluation in a Phase I dose-escalation study in patients with tumors showed that DCP was tolerated at doses ranging from 100 to 550 mg/m2 and showed potential efficacy in Chinese cancer patients. DCP showed favorable bioavailability and stability in vivo, with the recommended Phase II dosage for DCP-containing chemotherapy being 450 mg/m2. DCP is currently being investigated as a monotherapy in several cancer types, such as prostatic carcinoma, and in combination with paclitaxel in a Phase II non-lung cancer study. The chemical structure of DCP is shown as formula I:

Dicycloplatin (DCP) was first reported in U.S. Pat. No. 6,699,901, which disclosed the chemical structure and process for preparation of DCP.
The crystal structure of DCP has been determined and reported in “Structural studies of dicycloplatin-an antitumor supramolecule.” Yang X. et al., Science China Chemistry, 40(5): 485-491 (2010), which shows dicycloplatin as a co-crystal composed of carboplatin and 1,1-cyclobutane dicarboxylate.
However, the processes disclosed in U.S. Pat. No. 6,699,901, which were tested by the inventors of the present invention, cannot produce satisfying results and are difficult to scale up for industrial-scale production. The preparation of dicycloplatin according to the method of U.S. Pat. No. 6,699,901 produced a mixture of carboplatin and dicycloplatin, resulting in high toxicity and unacceptable products.
Therefore, it is desirable to provide robust and easy-to-scale-up crystallization processes to efficiently obtain pure dicycloplatin in high yield.